The purpose of this research study is to test the safety and effectiveness of the study drug, resmetirom, in participants with MASLD and HIV. This is a research study to test a drug that is already on the market with a population that was not included in the original clinical trials. Participants will be people over age 18 with HIV who are on antiretroviral therapy and have been diagnosed with MASLD.

Researchers will compare resmetirom to placebo (a look-alike substance that contains no drug) to see if resmetirom decreases the amount of fat in the liver.

Participants will:

• Complete 3 screening visits to determine eligibility.
• Take resmetirom or placebo every day for 24 weeks if eligible.
• Have 2 MRI scans to measure the amount of fat on the liver. One will be before treatment starts and one will be at the end of 24 weeks of treatment.
• Attend 3 scheduled clinic visits while on treatment for bloodwork and safety assessments.
• Participate in 3 phone calls while on treatment and one phone call 4 weeks after treatment is completed to check for safety and any health changes.

Inclusion Criteria:

1. Adults (≥18 years of age) with documented HIV.
2. Documented diagnosis of MASLD established by imaging (ultrasound, CT scan or MRI) or vibration-controlled transient elastography (VCTE) or liver biopsy within 12 months before screening.
3. Hepatic fat fraction ≥8% by MRI-PDFF.
4. Liver stiffness by VCTE ≥8 kPa and CAP≥263 dB/m
5. HIV-1 RNA <200 copies/mL for ≥6 months on antiretroviral therapy (ART) (must have screening HIV-1 RNA value and one clinical care value within 6 months prior to screening and up to the randomization that meet the criteria).
6. Stable ART regimen for ≥3 months prior to screening and stable up to the randomization and no active plans to change ART while on study.
7. Willingness to participate in the study.

Exclusion Criteria:

1. History of significant alcohol consumption (defined as >2 drinks/day on average for men, >1 drinks/day on average for women) for at least 3 consecutive months (12 consecutive weeks) within 5 year before screening

2. History of other acute or chronic liver disease, including, but not limited to autoimmune, primary biliary cholangitis, Wilson's disease, alpha 1 antitrypsin deficiency, hemochromatosis, hepatitis B virus (HBV), and ongoing or recent (within the past 3 years) hepatitis C RNA positivity.

3. History of liver transplant.

4. Liver biopsy or radiologic imaging consistent with the clinical presence of cirrhosis or portal hypertension at screening.

5. Participants whose Visit 2 ALT, AST, or alkaline phosphatase (ALP) values exceed their Visit 1 values by more than 50%.

6. Inability to undergo MRI testing

7. Uncontrolled T2DM defined as glycated hemoglobin (HbA1c) >9.5% at screening.

8. Any of the following laboratory values at screening:

   1. ALT or AST >250 U/L.
   2. Total bilirubin (TBL) >1.5 mg/dL and direct bilirubin > 0.5 mg/dL (unless due to Gilbert's disease or atazanavir use, per the opinion of the site investigator).
   3. Platelet count <150,000/mm3.
   4. Estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73m2 using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation
   5. International normalized ratio (INR) >1.3.
   6. Albumin < 3.6 g/dL

9. Liver stiffness measurement (LSM) by VCTE > 20 kPa

10. Further exclusion criteria apply

Await IRB determination of privacy and HIPAA issues